Over a recent number of years, there has been a strong movement within the surgical community toward minimally invasive therapies. The main goals of the minimally invasive therapies include: 1) eradication of targeted tissue, 2) decreased hospitalization time, 3) limited postoperative morbidities, 4) shortened return interval to daily functions and work, and 5) reduced overall treatment cost.
Cryotherapy and cryosurgery (i.e. cryogenic treatments) are currently utilized for thousands of patients annually. The treatment provides a minimally invasive method of treating a disease state through tissue freezing as opposed to surgical treatment or radiation therapy. Numerous disease states include organ confined tumors such as prostate, kidney, liver, as well as cardiovascular disease, retinal detachment, pain management, and other illness/disease states such as cancer and cardiovascular disease.
Evidence demonstrates that standard therapies provide less than optimal efficacy in the treatment of prostate cancer (Moul, J., 1999; Van den Ouden et al., 1998). Prostate cancer (CaP) is the second leading cause of cancer-related death in men in the United States with more than 225,000 new cases diagnosed annually, approximately 40,000 resulting in death (Carter and Isaacs, 2004; Oh, 2000; Petrylak, 1999). CaP is often treated initially with androgen ablation. Unfortunately, androgen ablation is not curative in many patients and the disease recurs in later years. Subsequent to anti-androgen failure, radical prostatectomy and radiation therapy (external beam or brachytherapy) provide treatment options for localized prostate cancer. Additionally, there is often a high complication rate associated with these procedures characterized by high morbidity, long hospital/therapeutic intervals, incontinence, loss of potency, and additional adverse side effects. Given the high number of annual cases of CaP and the high recurrent rate, the appropriate resources need to be gathered to develop and improve primary and salvage treatment options.
Cryotherapy is an effective yet minimally invasive alternative to current surgical procedures and radiation therapy approaches. The surgical procedure is done under either general or epidural anesthesia and offers patients a quicker recovery and reduced severity of potential side effects. For example, cryogenic treatment of prostate cancer reduces or potentially eliminates side effects such as incontinence. Without the expense associated with major surgery or an extended hospital stay, cryosurgery is a cost-effective treatment option. The treatment is highly effective for low, moderate and high risk localized prostate cancers. Impotence, however, remains an expected side effect of targeted cryosurgery due to the freezing of tissue outside the gland to kill cancer cells that may have spread.
The approaches described thus far related to cryotherapy have focused around the development of devices which utilize stainless steel cryoprobes inserted into a target tissue, activation of a machine which circulates a cryogen (such as argon or liquid nitrogen) in the probe to create a heat sink thereby resulting in tissue freezing. Once freezing is complete, the probes are removed and the tissue left to die. None of the previous attempts have considered the nature of the cell/tissue death involved and the potential ways to manipulate the destruction of diseased tissue. In order to successfully reduce the positive freeze margin, methods or approaches are needed to elevate the critical killing temperature or cryosurgical “dose”. The elevation of the critical kill temperature will not only apply to the freeze margin but also to specific locations within the tumor itself (i.e. neurovascular bundles). Targeting and enhancing specific cell death pathways involved with cryoablation through the combination of known cytotoxic agents can result in multiple cell stresses.
In addition, recent data demonstrate that when sub-lethal doses of cytotoxic agents applied in vitro, such as TNF-Related Apoptosis-Inducing Ligand (TRAIL), are applied in combination with freezing, complete prostate cancer cell death occurs. This enhanced cell death is in large part attained by the manipulation of the apoptotic, gene regulated, death cascade. Using this method, the critical death temperature has been reduced from −40° C. to −10° C.
The fundamental challenges faced by physicians using cryosurgery as a treatment for cancer revolve around the physics of the iceball produced, the surrounding anatomy, and the mechanisms of cellular destruction. Major anatomical structures, including the urethra, urinary bladder, rectal wall, and nerve bundles affecting erectile function, can be compromised during the procedure and result in secondary medical challenges to the patient (increased morbidity). To ensure complete ablation of the diseased tissue, however, physicians need to freeze a significant area beyond the disease margin. Many improvements have been made including monitoring of the freeze zone advancement and the use of a urethral warming device. While the warming device has led to a decreased incidence of incontinence, this device may impede cellular destruction within the tumor near the urethra.
The nature of cryosurgery generally requires a temperature of −40° C. or colder to ensure complete cell and tissue destruction. In order to achieve this “dose” during a typical cryosurgical procedure, the ice front or positive freeze margin should extend from 2-5 mm beyond the targeted tissue. This necessary positive freeze margin leads to significant damage to adjacent healthy tissue and unwanted patient side-effects. A variety of approaches have been developed in an attempt to minimize the freeze margin. Some of these include a change in the design of the probe resulting in different sized iceballs, an increase in the number of probes used for each procedure to produce a more uniform iceball, and multiple freeze-thaw cycles. While each of these techniques has led to some improvement in the efficacy of the procedure, none of them have been successful at completely negating the need to extend the freeze zone. Some of the major drawbacks include the physics of the ice formation and the isotherms generated, individuality amongst patients, and differences between physician applications, all of which lead to inconsistent results.
There exists a need for improvements in cryotherapy, and medical devices or components associated with the treatment to better facilitate and improve measures for treatment and cost. Studies are necessary to demonstrate that combining therapeutic strategies can increase the efficacy compared to each as a single agent. The combination of various chemotherapeutic agents includes potential benefits of combining classical cryosurgery and chemotherapy. The use of adjuvant methods has the potential to significantly reduce the need to extend the freeze margin while attaining enhanced efficacy. Having the ability to target specific sites within or around the tumor will help to protect those areas not intended to be destroyed.
As cryosurgery continues to gain acceptance, future improvements to the design and application will be desired to significantly improve its usage in prostate cancer as well as for the treatment of multiple other types of organ-confined tumors. While present treatments typically use cryosurgery as the sole therapy or as a single procedure, innovation and future developments will recognize the benefits of combination (neoadjunctive) therapies, including various therapeutic benefits in the control and eradication of cancerous tumors.
The medical device and methods of the present invention will allow for the simultaneous application of cryotherapy and cytotoxic agent therapy in a novel delivery system. The invention will desirably allow for the insertion of single or multiple delivery systems to produce a destructive treatment and/or freeze zone. Further, the invention will provide for a resorbable system or probe to more specifically target the designated tissue. The invention will facilitate the ablation or eradication of tissue, decrease procedural related side effects, increase therapeutic efficacy, decrease hospitalization time, limit postoperative morbidities, shorten return to daily functions and work, and further reduce the overall treatment cost. Desirably, these improvements to device design and application will also increase its utilization for the treatment of multiple disease states.